CZ69494A3 - Sparfloxacine solution, process of its preparation and a sparfloxacine salt - Google Patents

Abstract

Pharmaceutical composition consisting of a stable aqueous solution of the sparfloxacin of formula: <IMAGE> containing - sparfloxacin, - one or more monocarboxylic polyhydroxyacids or lactone derivatives thereof, at least in a stoichiometric quantity relative to the sparfloxacin, - if necessary, an excess of monocarboxylic polyhydroxyacid or of another pharmaceutically acceptable acid intended to ensure a pH for complete solubilisation of the salt thus formed, less than or equal to 5, - optionally, an isotonising agent and/or other pharmaceutically acceptable adjuvants.

Description

Region_the Cohorts

The invention relates to a new pharmaceutical composition suitable for parenteral administration of sparfloxacin.

/ techniques

Patent application EP 221 463 discloses a sparflo17.5 µm formula

COOH as well as its acid addition or base addition, useful as antimicrobial agents.

Patent application δ. EP 284 935 also describes quinolones and their salts and among them sparfloxacin.

Unfortunately, sparfloxacin salts are usually sparingly soluble or unstable in solution. Therefore, it has hitherto not been possible to prepare compositions useful for parenteral administration.

In European Pat. No. SP 322,892, all of these difficulties are mentioned and lyophilized compositions are described which comprise a sparfloxacin acid salt. However, it is not possible to prepare solutions that are stable over a longer period of time with these compositions; for this reason, it is only possible to prepare the solution as needed. Moreover, these solutions are at risk of being unsuitable for use in long-term perfusions.

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The present invention relates to stable injectable solutions. The granular compositions may be stored for a long time and are substantially heat resistant.

The solutions of the invention are aqueous solutions comprising: sparfloxacin, one or more monocarboxylic polyhydroxy acids or a lactone derivative thereof, at least in a stoichiometric amount based on sparfloxacin, if necessary, an excess of the monocarboxylic polyhydroxy acid or other pharmaceutically acceptable acid to provide such pH wherein the resulting salt is perfectly soluble and which is less than or equal to 5, optionally an isotonizing agent and / or other pharmaceutically acceptable excipients.

The solutions according to the invention contain at least 10 wt. sparflo xacinu. However, they may contain sparfloxacin in concentrations up to 40 phy%. It is also possible to prepare solutions with a concentration of less than 1% by weight, which are also clinically useful; these solutions are also included within the scope of the invention.

The monocarboxylic polyhydroxy acid is selected such that its pK? Value is greater than 3 at 25 ° C. For example, it may be selected from the group consisting of lactobionic acid, glucoheptonic acid, gluconic acid or ascorbic acid.

The amount of monocarboxylic polyhydroxy acid is a function of the amount of sparfloxacin. It is usually determined so as to achieve at least a stoichiometric ratio and, in particular, to obtain solutions with a pH of not less than 3.5.

The acid which ensures perfect solubility may be selected from the group consisting of pharmaceutically acceptable, non-hazardous acids, taking into account their nature and / or concentration to significantly replace the sparfloxacin monocarboxylic polyhydroxy acid salt. For example, they may be selected from organic acids such as acetic acid, propionic acid, tartaric acid, succinic acid, or monocarboxylic hydroxy or polyhydroxy acids. Among the stronger acids, in particular, sulfonic acids (e.g. methanesulfonic acid), dicarboxylic acids (e.g. maleic acid, oxalic acid or malonic acid), or inorganic acids (e.g. hydrochloric acid, phosphoric acid, sulfuric acid) may also be used, e.g. when their concentration can be fixed so that there is no risk of replacing the salt of sparfloxacin with a monocarboxylic polyhydroxy acid to a significant extent. It is convenient and convenient that the solubility and pH of the solution can be ensured by the monocarboxylic polyhydroxy acid used,

The solutions have a pH of less than or equal to 5. In general, the pH of the solutions should be compatible with direct application.

It is preferably in the range from 3.5 to 5.0.

Preferably, the solutions of the invention are isotonic. However, solutions that are not isotonic and which are intended to be perfused with glucose are also within the scope of this invention.

The solutions of the invention may be isotonized by the addition of an isotonizing agent such as glucose, glycerol, sorbitol, mannitol, xylitol, fructose or lactose.

The solutions according to the invention are primarily intended for parenteral administration. They can also be applied orally, in the eyes or ears, or they can be applied topically to the skin or mucous membranes.

It is also possible for the solutions of the invention to contain other compatible and pharmaceutically acceptable additives in addition to the isotonizing agent. They may contain, for example, sweeteners, flavoring agents, preservatives, coloring agents and optionally gelling agents.

Obviously, the obtained monocarboxylic acid sparfloxacin salts, which allow the preparation and use of stable injectable solutions, are also included within the scope of the present invention.

The solutions of the invention may be prepared either. adding water to the mixture containing sparfloxacin, one or more selected monocarboxylic polyhydroxy acids, at least in a stoichiometric amount based on sparfloxacin, or an excess of mono- 4 carboxylic polyhydroxy acid or other acid to provide a pH lower for solubilizing the sparfloxacin salt which is lower than 5 or equal to 5 and / or isotonizing agent and other additives, or also by adding sparfloxacin and optionally other additives to a solution of one or more monocarboxylic polyhydroxy acids.

The preparation and adjustment of the solution is preferably carried out under a nitrogen atmosphere. The solutions thus obtained can be heat sterilized (autoclaved). However, in the case of ascorbic acid salt solutions, it is preferable to use filter sterilization.

It is also possible to prepare the solutions of the invention using acid derivatives of lactones, from which hydrolysis in situ results in monocarboxylic polyhydroxy acids.

The solutions according to the invention are advantageous for their very good physical-chemical stability. They are of particular interest in making liquid formulations of sparfloxacin available, which hitherto has not been possible, in particular an injectable formulation which is light-stable under normal conditions of use and heat and always has a pH value that is acceptable for direct application. This new formulation is advantageous for storage, for convenient and rapid application in ready-to-use form and also for cases of slow perfusion. Among other things, also due to the good solubility of the salts obtained from. Under the conditions given by the pH used, the solutions may have a higher concentration, allowing a variety of prescribed doses to be chosen.

The following examples illustrate the invention but do not limit it in any way.

Examples of the present invention

Example 1

Preparation of a solution containing 4 mg / ml sparfloxacin isotonized with glucose

400 mg of sparfloxacin are mixed with 321 mg of glucono-delta-lactone and 4.75 g of glucose monohydrate. This powder mixture is dissolved in water for injection, previously purged with nitrogen. Dissolution is achieved by stirring under a nitrogen atmosphere. Make up the volume to 100 ml with water for injections. The solution thus obtained is sterilized in an autoclave (120 ° C, 20 min). The solution has a pH of 3.8. This solution is clear even after 5 months of storage at 4, 20 and 35 ° C without changing the pH.

Example 2

Preparation of a solution containing 10 mg / ml sparfloxacin, isotonized with glucose

The procedure is as in Example 1 above, but the volume is brought up to 40 ml using 1.74 g of glucose monohydrate. A clear solution with a pH of 3.8 was obtained. This solution, prepared in an amount of 2.5 liters, remains clear and unchanged for at least 5 months at the following temperature conditions: 20, 4 and 35 ° C. HPLC analysis after 3 months storage at 20, 4, 35 and 45 ° C showed no degradation of the product.

Example 3

Preparation of a solution containing 20 mg / ml sparfloxacin isotonized with glucose

The procedure is as in Example 1 above, but the volume is brought up to 20 ml and 770 mg of glucose monohydrate is added; prepare a clear solution having a pH of 3.7. This solution, prepared in an amount of 2 liters, remains clear and unchanged after 3 months of storage at 20, 4, 35 and 45 ° C. HPLC analysis after 1 month storage at 20, 35 and 45 ° C showed no degradation of the product.

Example 4

Preparation of a solution containing 50 mg / ml sparfloxacin, isotonized with glucose

The procedure is as in Example 1, but the volume is brought up to 8 ml and 130 mg of glucose monohydrate is added; prepare a clear solution having a pH of 3.5. This solution, prepared in an amount of 2 liters, remains clear and unchanged pH after 3 months storage at 20, 4, 35 and 45 ° C. HPLC analysis after 1 month storage at 20, 35 and 45 ° C showed no degradation products.

Example 5

Preparation of hypertonic solution containing 100 mg / ml sparfloxacin

The procedure is as in Example 1, but the volume is made up to 4 ml without the addition of glucose; a solution having a pH of 3.5 is prepared. This solution, prepared in an amount of 1 liter, remains clear and unchanged pH after 3 months storage at 20, 4, 3 and 45 ° C. HPLC analysis after 1 month stored at 20, 35 and 45 ° C showed no degradation products.

Example 6

Preparation of hypertonic solution containing 200 mg / ml sparfloxacin

The procedure is as in Example 1, but the volume is made up to 2 ml without the addition of glucose; prepare a clear solution having a pH of 3.5. This solution, prepared in an amount of 1 liter, remains clear and unchanged after 3 months storage at 20, 435 and 45 ° C. HPLC analysis after 1 month storage at 20, 35 and 45 ° C showed no degradation products.

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- 7 Example 7

Preparation of a solution containing 10 mg / ml sparfloxacin

1000 mg of sparfloxacin are mixed with 1.79 g of lactobionic acid. This powder mixture is dissolved in water for injection, previously purged with nitrogen. Dissolution is achieved by stirring under a nitrogen atmosphere. Make up the volume to 100 ml with water for injections. The solution thus obtained is sterilized in an autoclave (120 ° C, 20 min). The solution has a pH of 3.75. This solution remains clear after 5 months of storage at 4 and 20 ° C and unchanged pH. HPLC analysis after 5 months of storage showed no degradation by degradation products.

Example 8

Preparation of a solution containing 20 mg / ml sparfloxacin

The procedure is as in Example 7, but 2000 mg of sparfloxacin and 3.58 g of lactobionic acid are used and the volume is made up to 100 ml; a clear solution having a pH of 3.5 is obtained.

Example 9

Preparation of a solution containing 30 mg / ml sparfloxacin

The procedure was as in Example 7, but using 3000 mg of sparfloxacin and 8.96 g of lactobionic acid, and after bringing the volume up to 100 ml, a clear solution having a pH of 3.5 was obtained.

Example 10

Preparation of a solution containing 10 mg / ml sparfloxacin

The procedure is as in Example 7, but using 1000 mg of sparfloxacin and 2.26 g of glucoheptonic acid and filling the volume to 100 ml; after heating at 50 ° C for 1 h, a clear solution is obtained with a pH = 4.3.

Example 11

Preparation of a solution containing 10 mg / ml sparfloxacin, isotonized with glucose

1000 mg of sparfloxacin are mixed with 528 mg of ascorbic acid and 4 g of anhydrous glucose. This powder mixture is dissolved in water for injection, previously purged with nitrogen. Dissolution is achieved by stirring under a nitrogen atmosphere. Make up the volume to 100 ml with water for injections. The solution thus obtained is sterilized by filtration. The solution has a pH of 4.8. This solution, stored for 7 months at 4 and 20 ° C, in the absence of light, remains clear and unchanged pE. HPLC analysis after 7 months of storage did not show contamination by degradation products.

Example 12

Preparation of a solution containing 10 mg / ml sparfloxacin, isotonized with glycerol

The procedure is as in Example 11, but using 2-2 g of glycerol in place of glucose to give a clear solution having a pH of 5. This solution is clear after 7 months storage at 4 and 20 ° C, no light, unchanged pH. HPLC analysis after 7 months of storage did not show contamination by degradation products.

Example 13

Preparation of a solution containing 20 mg / ml sparfloxacin

The procedure is as in Example 11, but using 2000 mg of sparfloxacin and 1.76 g of ascorbic acid. A clear solution is obtained with a pH value of 4.2. This solution remains clear after 7 months of storage at 20 ° C, in the absence of light.

Rp &lt; 2 &gt;

The present invention makes it possible to prepare new salts of antimicrobially active sparfloxacin, in particular monocarboxylic polyhydroxy acids, and aqueous solutions thereof, which are stable without changing pH for a relatively long time and which facilitate parenteral administration, even by long-term perfusion.

Claims (10)

PATENT CLAIMS A stable aqueous solution of sparfloxacin of formula • COOH, characterized in that it comprises: sparfloxacin, one or more monocarboxylic polyhydroxy acids or a lactone derivative thereof, at least in a stoichiometric amount, based on sparfloxacin, if necessary, an excess of the monocarboxylic polyhydroxy acid or other pharmaceutically acceptable acid, providing such a value at which the salt formed is perfectly soluble and less than or equal to 5% optionally an isotonizing agent and / or other pharmaceutically acceptable excipients. in ic eu The solution according to claim 1, characterized in that the monocarboxylic polyhydroxy acid is selected from the group of acids having a pK? Value greater than 3 at 25 ° C. The solution according to claim 1 or 2, wherein the monocarboxylic polyhydroxy acid is selected from the group consisting of acid acid lactobionic acid, gluconic acid, gluconic acid or ascorbic acid. A solution according to claim 1, characterized in that it contains sparfloxacin in a concentration of up to 40% by weight. A solution according to claim 1 having a pE in the range of from 3.5 to 5.0. The solution of claim 1, wherein the isotonizing agent is selected from the group consisting of glucose, glycerol, sorbitol, mannitol, xylitol, fructose or lactose. 7. A process for preparing a solution according to claim 1, wherein the mixture of sparfloxacin with one or more monocarboxylic polyhydroxy acids is at least stoichiometric based on the amount of sparfloxacin and optionally with an excess of monocarboxylic polyhydroxy acid or another acid to provide such a pH, in which the salt is perfectly soluble and which is less than or equal to 5 and / or with an isotonizing agent or other additives, is added to the water. A process for the preparation of a solution according to claim 1, characterized in that the sparfloxacin and optionally the acid ensuring a pH at which the salt is perfectly soluble and which is less than or equal to 5 and / or isotonizing agent and other additives , add to the solution one or more monocarboxylic polyhydroxy acids. A salt of sparfloxacin with a monocarboxylic polyhydroxy acid selected from the group consisting of lactobionic acid, glucoheptonic acid, ascorbic acid. A pharmaceutical composition comprising a solution according to claim 1, optionally in combination with one or more compatible and pharmaceutically acceptable diluents or excipients.